This Training Program provides graduate students with advanced education in the principles and practice of macromolecular chemistry, mechanism, and structure. All aspects of the program - formal course curriculum, laboratory rotations, informal specialized area-interest seminars, and intensive research in laboratories operating on the edge of discovery - are aimed at the question: how do biological macromolecules work? How do proteins, membranes, nucleic acids, and high-order complexes of these huge molecules use physical-chemical and structural principles to act in the enormous variety of contexts that underlie biological function? The Training Program provides support for selected students in the Graduate Program in Biochemistry and Biophysics at Brandeis University. This is a flexible PhD program designed for two broad types of students: those with strong quantitative backgrounds but who may have weaker prior training experience in biological chemistry, and those with more traditional training in biochemistry and cell biology. Our intention is to bring these two groups of students to the same end-point and to prepare them for careers in basic research. Currently, 3 students (which will rise to 35 students in September '14) are enrolled in this Ph.D. program; the Training Program includes 26 participating faculty (in four departments) working in the following areas: macromolecular structure determination by x-ray crystallography and NMR, mechanistic enzymology, membrane transport and ion channel mechanisms, single-molecule analysis, high- resolution mass spectroscopy and proteomics, computational biophysics, protein evolution.